Genetically engineered antibodies help block SARS-CoV-2 infection

The modified FuG1 antibody competitively interferes with the furin function required for the SARS-CoV-2 virus to become highly contagious. Credit: UC Davis

Researchers at the University of California, Davis have designed a new antibody, FuG1, that can directly interfere with the intercellular transmission capacity of SARS-CoV-2, the virus that causes COVID-19.

FuG1 targets the enzyme furin. virus Used for an efficient chain of infections in human cells. This approach can be added to existing SARS-CoV-2 antibody cocktails to enhance their function against new mutants.

A study to evaluate the efficacy of genetically engineered antibodies was published today Microbiology spectrum..

“We have developed an approach that disrupts the SARS-CoV-2 transmission chain. The COVID-19 vaccine is a great lifesaver in reducing hospitalization and serious illness. But we are now them. Is infectious of the virus. “

Tushir-Singh is an associate professor in the Department of Medical Microbiology and Immunology and a member of the UC Davis Comprehensive Cancer Center Treatment Program.His research uses rational protein engineering to generate multi-targeting. antibody As a cancer treatment. When a pandemic occurred, he began to think of similar strategies that might help limit the spread of the coronavirus.

Enzyme activates SARS-CoV-2 spike protein

Wind chimes found throughout the human body are involved in various functions of cells. It is a type of enzyme, a protease that can break down proteins into smaller components. This is done by breaking or breaking the multibasic peptide bond within the protein.

In breaking these bonds, furins often act as switches, turning inactive proteins into active proteins. For example, furin cleaves inactive parathyroid hormone into parathyroid hormone, which regulates blood calcium levels.

It can also cut and activate invading viruses. Human cells..Pathogens that utilize furin Human host Includes HIV, influenza, dengue fever and SARS-CoV-2.

COVID-19 virus abuses host furin system

When SARS-CoV-2 infects human cells, SARS-CoV-2 becomes active and has already been “cleaved”. Spike proteinAn important protein that binds to and invades the ACE2 receptor.

However, when the virus is synthesized in the host cell, that is, when it is replicating, spike It is inactive. The virus must use the host cell’s furin to cleave the peplomer into two parts, S1 and S2. This activates the spikes on the virus particles and propagates efficiently upon release.

“The virus uses the wind chimes of the host to infect one cell to another. This additional activation step makes the virus very susceptible to transmission,” said the lead author of the study. Tan Moi Mondal, a postdoctoral fellow at the University of California, Davis, said. ..

However, inhibiting furin to limit the SARS-CoV-2 linkage in the infection cycle is not an easy mechanism.

“Foorin can be found everywhere human body And it is necessary for the normal functioning of many biological processes. Stopping furin from doing its job causes high body toxicity. As a result, standard furin inhibitors are not a clinically viable option, ā€¯Tushir-Singh said.

Instead, he and his team designed a binding antibody that targets the SARS-CoV-2 peaplomer. The design is similar to a Therapeutic Monoclonal (IgG) antibody, but contains an additional function (Fc extended peptide) that specifically interferes with the host’s furin. Researchers have named this approach FuG1.

FuG1 allows disruption of furin function to limit the activation of spikes, and thus specifically limits the infectivity of the virus during the chain of infection in the host cell. The High affinityThe FuG1 variable domain targeting spike is the key to furin targeting specificity to avoid potential toxicity.

Antibodies interfere with spike cleavage and stability

The team evaluated FuG1, a furin-destroying agent engineered on human lung tissue cells. The test was performed using the original SARS-CoV-2 variant and a pseudovirus. They found it:

  • The addition of the furin-destroying peptide did not interfere with the function of the antibody or its ability to bind SARS-CoV-2 spikes.
  • FuG1 had a significant effect on spike cutting at the furin site.
  • FuG1 further hampered the overall stability of the SARS-CoV-2 spike proteinThis is generally required for cell infection and virus transmission.

The next step for the team is a series of experiments with mice. They also test antibodies engineered against current variants such as Omicron.

Tushir-Singh is cautiously optimistic that variants such as Omicron do not make much of a difference. “FuG1 antibody is logical to target furin spike cleavage, a newly acquired biological component of SARS-CoV-2 infectivity. Our approach is to target the emerging SARS. -CoV- The two variants do not interfere with the binding of FuG1 antibodies. This type of strategy is likely to interfere with the transmission of the virus, “said Tusir-Singh.

In addition to targeting SARS-CoV-2, Tushir-Singh believes that this approach can be applied to future coronaviruses and other viruses that infect using proteases such as furin. .. cell Because of their pathology.

NIH scientists identify mechanisms that may affect the infectivity of SARS-CoV-2 mutants

For more information:
Tanmoy Mondal et al, a viable alternative strategy targeting furin disrupts the SARS-CoV-2 infection cycle, Microbiology spectrum (2022). DOI: 10.1128 /spectrum.02364-21

Quote: Manipulated antibody transmitted SARS-CoV-2 obtained on February 11, 2022 from https: // ( Helps block (February 11, 2022)

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Genetically engineered antibodies help block SARS-CoV-2 infection

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